AU651701B2 - Method for preventing restenosis following reconfiguration of body vessels - Google Patents
Method for preventing restenosis following reconfiguration of body vessels Download PDFInfo
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- AU651701B2 AU651701B2 AU18753/92A AU1875392A AU651701B2 AU 651701 B2 AU651701 B2 AU 651701B2 AU 18753/92 A AU18753/92 A AU 18753/92A AU 1875392 A AU1875392 A AU 1875392A AU 651701 B2 AU651701 B2 AU 651701B2
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- psoralen
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- recanalization
- ultraviolet radiation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N5/0601—Apparatus for use inside the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N5/0613—Apparatus adapted for a specific treatment
- A61N5/062—Photodynamic therapy, i.e. excitation of an agent
Abstract
Restenosis following vascular recanalization is prevented by administering a photoactivatable psoralen and, in conjunction with recanalization, delivering ultraviolet radiation to the region of said recanalization.
Description
OPI DATE 17/11/92 APPLN. ID 18753/92 AOJP DATE 21/11/92 PCT NUMBER PCT/US92/02820 Ill lllll ll AU92 111111 1 1 l AU9218753 II L~11.~ILV.1 L II~lr 1L. VYIVLIU V YL 11I 1 ~~VVL I11 I\I k1 (51) International Patent Classification 5 A61K 31/35 Al (11) International Publication Number: (43) International Publication Date: WO 92/18122 29 October 1992 (29.10.92) (21) International Application Number: (22) International Filing Date: PCT/US92/02820 7 April 1992 (07.04.92) Priority data: 682,627 9 April 1991 (09.04.91) (71)Applicant: INDIANA UNIVERSITY FOUNDATION [US/US]; Showalter House, P.O. Box 500, Bloomington, IN 47402 (US).
(72) Inventors: MARCH, Keith, L. 13611 Snringmill Boulevard, Carmel, IN 46032 HATHAWAY, David, R. 7966 North Illinois Street, Indianapolis, IN 46260 (US).
WILENSKY, Robert, L. 5011 Westwood Circle, Carmel, IN 46032 PATTON, Brian, L. 316 West Main, Thorntown, IN 46071 (US).
(74) Agents: HOFFMAN, John, F. et al.; 2400 Fort Wayne National Bank Building, Fort Wayne, IN 46802 (US).
(81) Designated States: AT (European patent), AU, BB, BE (European patent), BF (OAPI patent), BG, BJ (OAFI patent), BR, CA, CF (OAPI patent), CG (OAPI patent), CH (European patent), CI (OAPI patent), CM (OAPI patent), DE (European patent), DK (European patent), ES (European patent), FI, FR (European patent), GA (OAPI patent), GB (European patent), GN (OAPI patent), GR (European patent), HU, IT (European patent), JP, KP, KR, LK, LU (European patent), MC (European patent), MG, ML (OAPI patent), MR (OAPI patent), MW, NL (European patent), NO, PL, RO, RU, SD, SE (European patent), SN (OAPI patent), TD (OAPI patent), TG (OAPI patent).
Published With international search report.
Before the expiration of the time limit .for amending the claims and to be republished in the event of the receipt of amendments.
701 ii d: i (54) Title: METHOD FOR PREVENTING RESTENOSIS FOLLOWING RECONFIGURATION OF BODY VESSELS (57) Abstract Restenosis following vascular recanalization is prevented by administering a photoactivatable psoralen and, in conjunction with recanalization, delivering ultraviolet radiation to the region of said recanalization.
I WO 92/18122 PCT/US92/02820 -1- METHOD FOR PREVENTING RESTENOSIS FOLLOWING RECONFIGURATION OF BODY VESSELS A number of procedures have been developed to recanalize at least partially occluded blood vessels by dilation or clearing of occlusive material. These procedures utilize, alone or in combination, balloon, laser, thermal, ultrasound, non-balloon mechanical atherectomy) or stenting devices. All rely on some form of mechanical violence to the vascular wall which, in early or delayed consequence, produces an undesirably high incidence of restenosis at or near the injured site. This situation prevails despite the high levels of sophistication represented in angioplasty (stenosis reduction) device technology and its application.
Numerous studies have implicated the uncontrolled proliferation of smooth muscle cells within the arterial wall resulting from injury initiated by angioplasty as a prominent factor in restenosis as well as the formation of the initial atherosclerotic lesion.
Included in approaches to the problem of the initial occlusion have been attempts to achieve inhibition of smooth muscle cell proliferation by administration of photoactivatable chemical agents which provide some degree of cytotoxic reaction. This work has chiefly centered on hematoporphyrin and its derivatives. For example, dihematoporphyrin ester and ether exhibit greater inhibition of plaque cell proliferation in culture than proliferation of smooth muscle cells derived from nonatherosclerotic arteries, suggesting an increased activity against plaque cells. Dartsch et al., Differential Effect of Photofrin II On Growth Of Human Smooth Muscle Cells From Nonatherosclerotic Arteries And Atheromatous Plaques In Vitro, 1.^ WO 92/18122 PCT/US92/02820 -2- Arteriosclerosis 10:616 (1990). Also, ultraviolet radiation of hematoporphyrin ester and ether has been found to intensify destruction of smooth muscle cells from atherosclerotic plaque as compared with nonatherosclerotic arterial cells. Dartsch et al., Responses Of Cultured Smooth Muscle Cells From Human Nonatherosclerotic Arteries And Primary Stenosing Lesions After Photoradiation: Implications For Photodynamic Therapy of Vascular Stenoses, J. Am. Coll.
Cardiol. 15:1545 (1990).
Other laboratory studies have demonstrated selective absorption of hematoporphyrins by atheromatous plaques which, on irradiation, induce fluorescence that permits imaging of the plaques. U.S. Patent No. 4,577,636 (Spears). Animal studies have produced proposals for the destruction of atheromatous plaque by photoactivated hematoporphyrins. U.S. Patent Nos. 4,512,762 and 4,773,899 (Spears).
Despite promising laboratory results on the selective inhibition or destruction of atheromatous plaque, inherent properties of hematoporphyrins have mitigated against their use in humans. Numerous reports of treatment of various cancers have established the significant cytotoxic effect of hematoporphyrins as well as the need for caution to avoid cutaneous phototoxicity from systemic hematoporphyrin administration. In one study it was found that patients needed protection from light exposure "for several weeks after therapy" with systemic hematoporphyrin derivative in patients with diffuse transitional cell carcinoma of the bladder.
Benson, Treatment of Diffuse Transitional Cell Carcinoma in salt by Whole Bladder Hematoporphyrin Derivative Photodynamic Therapy, J. Urol. 134:675, 678 I
C-
WO 92/18122 PCT/US92/02820 -3- (1985). To the same effect with respect to duration of generalized photosensitization of patients in cancer therapy, see Dougherty et al., Photoradiation Therapy for the Treatment of Malignant Tumors, Cancer Res.
38:2628 (1978) ("up to 30 days"); Lam et al., Detetion of Early Luna Cancer Using Low Dose Photofrin II, Chest 97:333 (1990) minimum of 30 days"); Prout et al., Photodvnamic Therapy With Hematoporphvrin Derivative in the Treatment of Superficial Transitional Cell Carcinoma of the Bladder, New Eng. J. Med. 317:1251 (1987) ("four to six weeks"); and Razum et al., in Photosensitivity: Duration and Intensity Following Intravenous Hematoporphvrin Derivates. HPD and DHE, Photochem. and Photobiol. 46:925 (1987) weeks").
Although the hematoporphyrins have thus been shown to inhibit smooth muscle cell proliferation and to possess other qualities that would be useful in defending against atherosclerosis, the phototoxicity of hematoporphyrins does not commend its human use based on present knowledge in the art. Indeed, there is no currently available and practicable method for diminishing or prophylaxing the restenotic process.
It is, therefore, an object of this invention to provide a novel approach to preventing restenosis following recanalization of peripheral and cardiac vasculature by angioplasty, including dilation or clearing of occlusive material.
It is also an object to provide a photochemotherapeutic approach to preventing restenosis following such recanalization of peripheral and cardiac vasculature by conjunctive systemic administration of a photoactivatable agent with little cytotoxic effect which inhibits proliferation of smooth muscle cells on ultraviolet radiation.
WO 92/18122 PCT/US92/02820 -4- It is a further object to provide a method for preventing restenosis following recanalization of peripheral and cardiac vasculature using intraluminal catheters for delivering ultraviolet light to an arterial site at which a systemically administered psoralen is present in smooth muscle cells subject to hyperproliferation in the region of dilation.
It is an additional object to provide a method for preventing restenosis following coronary artery reconfiguration by balloon angioplasty in which a photoactivatable psoralen is delivered to the smooth muscle cells in the presence of ultraviolet radiation as a means for inhibiting smooth muscle cell proliferation in the region of coronary angioplasty.
It has now been discovered that photoactivatable psoralens significantly inhibit the proliferation of smooth muscle cells on irradiation with long-wave ultraviolet light (PUVA). Accordingly, this invention relates to a method for preventing restenosis in a subject undergoing vascular recan.lization which comprises administering a photoactivatable psoralen, reconfiguring at least a partially-occluded vessel, and delivering ultraviolet radiation to the region of I recanalization. By recanalization is meant a procedure for increasing blood flow through the occluded vessel J by angioplasty, including dilation or ablation or removal of occlusive material.
This novel method may be used with any form of recanalization of peripheral or cardiac vasculature utilizing, alone or in combination, balloon, laser, thermal, ultrasound, non-balloon mechanical (e.g.
atherectomy) or stenting devices. Conditions such as coronary artery occlusion, peripheral artery occlusion, arterial or venous graft occlusion and synthetic graft WO 92/18122 PCT/US92/02820 occlusion are appropriate candidates for treatment by the method of this invention.
The discovery that photoactivatable psoralens significantly inhibit the proliferation of smooth muscle cells on irradiation with ultraviolet light is a signal development in view of the fact that there is no currently available and practicable method for diminishing or prophylaxing the restenotic process in humans. The extensive recorded history of the use of systemically administered psoralens as the treatment of choice in psoriasis provides confidence that psoralens will find a significant place in preventing restenosis where smooth muscle cell proliferation is implicated as a causative factor.
Psoralens are known to provide workable safety margins with ultraviolet radiation in the A band range (PUVA) of about 320 to about 400 nm. The relatively short period of light sensitivity in subjects who have received psoralens and artificial PUVA (as compared, for example, with the prolonged sensitivity associated with the hematoporphyrins) is documented in numerous studies on the treatment of psoriasis and provides evidence that use of their combination as an adjunct to vascular recanalization in the prevention of restenosis presents no untoward complications. Psoralens are said to be cleared from the body in about 24 hours, with no photosensitivity inducible after 8 hours. Honigsmann, Photosensitizing Compounds: Their Chemistry. Biology and Clinical Use (1989), p. 143 (Wiley).
Manifestations of previously induced photoxicity have been reported as inflammation peaking at 48 72 hours.
Harber et al., Photosensitivity Diseases (1989), 69 (Decker); Stern et al., Psoriasis, Roenigk, Ed. (1991) 604 (Dekker).
WO 92/18122 PCT/US92/02820 -6- There has been wide speculation as to the mode of action of psoralens photoactivated by ultraviolet light in the treatment of psoriasis. It is known that photoactivated psoralens may form links with DNA to affect cell growth. Also, effects of UVA light on epidermal growth factor receptor binding is potentiated by psoralens. Laskin, Psoralens Potentiate Ultraviolet Light-Induced Inhibition of Epidermal Growth Factor Binding, Proc. Natl. Acad. Sci. 83:8211 (1986).
However, the mechanism by which irradiated psoralens inhibit smooth muscle cell proliferation has not been elucidated and is not advanced by the modulation of epithelial cell growth.
The molecular structure of psoralen admits of multisubstitution at numerous positions. Although in the practice of this invention, 8-methoxypsoralen is preferred, unsubstituted psoralen and other-substituted photoactivatable psoralens, identified by their ability to undergo bonding with cellular macromolecules DNA) and inhibit smooth muscle cell proliferation are appropriate for use herein. Examples of such psoralens are those substituted at one or more of the 3, 4, 4', 5' or 8 positions, such as 4-methylpsoralen, 4,4'-dimethylpsoralen, 4,5'-dimethylpsoralen, 4',8-dimethylpsoralen and 4,5',8-trimethylpsoralen. These further include pyrido-psoralens, 3-carbethoxy psoralens, 4'-lower alkoxy psoralens, 4-lower alkyl-8-amino-lower alkyl psoralens, 5' amino-alkyl psoralens and iso-psoralens (angelicins), as described in Gasparro, Psoralen DNA Photobioloqy (CRC Press, 1988) and U.S. Patent Nos. 4,321,919 (Edelson), 4,465,691 (Bisagni), 4,269,851 (Kaufman), 4,328,239 (Kaufman), 4,269,852 (Kaufman), 4,464,354 (Bisagni), 4,294,822 (Kaufman) and WO 92/18122 PCT/US92/02820 -7- 4,169,204 (Hearst), disclosure of which are incorporated herein by reference.
It is the psoralen's basic structure which confers the desired activity, with substituents enhancing or diminishing photoactivation and photosensitization.
Accordingly, giving consideration to these variables and possible idiosyncratic reactions to specific substituents, a wide range of selection is afforded by this class of compounds. Helpful discussions of the chemistry and photochemotherapy of psoralens and structures of other psoralens for consideration in this use are found in Harber et al., Photosensitivity Diseases (1989), Chapter 6 (Decker), and Anderson et al., Psoralen Photochemotherapv of Cutaneous Disorders, Ann. Rev. Pharmicol. Toxicol. 20:235 (1980).
The objective in psoralen administration is to achieve quickly the serum levels of psoralen found appropriate for light-dependent inhibition of smooth muscle cell growth. Should recanalization be recognized as immediately necessary during catheterization but before peak levels of psoralen are obtained, recanalization should proceed and be followed at the time of peak levels by a separate procedure directed to preventing restenosis.
Administration preferably is systemic by oral dosage to achieve serum levels from about 0.1 to about 10 AM, preferably from about 0.5 to about 2 AM, at which time radiation would be commenced. Individual doses in the range of from about 10 to about 100 mg in a single dose given about 30 minutes to 3 hours, preferably 1 to 2 hours, prior to arterial dilation are appropriate.
Single doses of from about 20 to about 70 mg given about one-half to about 1 hour prior to the procedure are preferred. Alternatively, a single intravenous I I i I. WO 92/18122 PCT/US92/02820 -8injection to give corresponding serum levels may be given about one-half hour before the procedure where oral administration is not feasible. Another alternative is the local intra-arterial injection of a psoralen via catheters such as those employed for delivering heparin, as described in U.S. Patent No. 4,824,436 (Wolinsky).
Catheters appropriate for use in accomplishing vascular recanalization and affording prope;ly focused ultraviolet radiation are exemplified by those catheters described for use in laser balloon angioplasty, in which provision for radiation to heat the area of dilation is incorporated. Such a catheter is described in U.S. Patent No. 4,799,479 (Spears), which is incorporated herein by reference. It is advantageous to employ a catheter with fiber-optics for transmission of the radiation that permits 360* exposure of the endoluminal surface of the artery to ultraviolet light. The typical fiber-optic employed in laser angioplasty may be adapted for present use by abrading at least a portion of the fiber-optic surface within the reconfiguring element balloon).
U.S. Patent Nos. 4,799,479 (Spears), 4,878,492 (Sinofski); Fujii et al., Light-Scattering Properties of a Rough-Ended Optical Fiber, Optics and Laser Technol. 40 (Feb.) 1984. This permits diffusion of radiation along the optical fiber instead of solely out the distal end, thus affording radiation at, rather than along, the targeted vascular surface.
It may be desirable to employ a catheter providing flow-through of arterial blood in order to avoid undue artificial occlusion during the process of recanalization and smooth muscle cell inhibition. In such event, perfusion catheters such as described in i WO 92/18122 PCT/US92/02820 -9- U.S. Patent Nos. 4,771,777 (Horzewski), 4,790,315 (Mueller) and 4,892,519 (Songer), modified to receive the fiber-optic for UVA transmission, may be employed.
Energy delivery at the catheter tip ranges from about 0.1 to about 10 J/cm 2 although empirical derivation can identify more precise levels. For example, if deeper effect is desired, elevated energy levels might be necessary to compensate for superficial absorbance of UV energy resulting from attenuation.
Another variable is the rate of energy delivery. In order to minimize occlusion time of the vessel during energy delivery, delivery time should be judged by the condition of the patient and other factors.
As a guide, the power input in W/cm 2 should be the desired J/cm 2 divided by the time in seconds. For example, 5 J/cm 2 desired over 5 seconds would require a power output of 1 W/cm 2 The power input at the proximal tip of the catheter would be determined by the area of illumination in cm 2 the catheter lengthattenuation constant, any focal losses at optical joints, and any attenuation determined to occur through the balloon and the substance used for inflation.
Generally, irradiation of a circumferential area of vessel wall of about 1.5 cm 2 delivered from the working area of the optical fiber, would require from about 0.15 to about 15 J in an appropriate combination of time and power. For example, 10 J over a period of seconds would require 1 W of power. Expressed in terms of the reciprocal relationship between power and time, exposure for 10 to 100 seconds would require power of 1 W to 0.1 W.
The discovery that the proliferation of smooth muscle cells is inhibited by photoactivating the reaction between a psoralen and smooth muscle cells has WO 92/18122 PCT/US92/02820 been demonstrated in studies of the effects of PUVA exposure on proliferation of bovine aortic smooth muscle cells. Observations were made over a 14-day period by trypan blue exclusion counts to determine cell proliferation and viability. Cell cycle effects were evaluated by thymidine incorporation and flow cytometry with DNA quantitation following the addition of serum to subconfluent cells synchronized by serum withdrawal.
No effect was observed following exposure of the cells to only 8-methoxypsoralen at concentrations up to MM or only UVA irradiation at energies up to 2 J/cm 2 Long-wave UV radiation and 8-methoxypsoralen were found to behave synergistically as potent inhibitors of DNA synthesis of the smooth muscle cells with the EC 50 in combinations rangin from 7 AM at 0.22 J/cm 2 to 0.2 MM at 1.4 J/cm 2 Similar antiproliferative effects were obtained by inverse variation of dose and energy.
Following serum stimulation, inhibition of DNA synthesis was found with either immediate or delayed (16 hours) application of PUVA. This was independent I of subsequent 8-methoxypsoralen washout. Flow cytometry showed this effect to occur via a block prior to S-phase in the synchronized cells. Evaluation of [125]-I- labeled platelet-derived growth factor (PDGF) binding revealed no effect of PUVA on the apparent number or affinity of binding sites present. Cell counting after a single exposure to PUVA (1 AM, 1 J/cm 2 revealed complete arrest of cell proliferation over a 14-day period without additional radiation. No increase in trypan-positive cells was noted over this period. These results show local inhibition of proliferation of vascular smooth muscle cells in j_ WO 92/18122 PCT/US92/02820 -11culture without evidence of increased cell death relative to untreated cells.
It is known that injury to the components of the vascular wall plays a central role in inciting the smooth muscle proliferative response resulting in restenosis. It is therefore important tc utilize antiproliferative agents in a manner achieving smooth muscle cell inhibition without undesirable cell destruction.
It will be appreciated by those in the art that the timing of the administration of a photoactivatable psoralen may vary with factors present at the time of the procedure. For example, the psoralen may be given either before or after recanalization. The important determinant is not the sequence of psoralen administration and recanalization but rather the essential presence of psoralen in the target tissue at the time of ultraviolet radiation. Considerations such as the route of administration of the psoralen, with the consequent variation in transport time to the desired site, against the practicalities facing the physician in a particular situation properly control the sequence. Those skilled in the art will recognize additional variations which may be interposed but which do not depart from the spirit or intent of this invention.
IL
Claims (14)
1. A method for preventing restenosis in peripheral or cardiac vasculature following vascular recanalization which comprises: systemically administering a photoactivatable psoralen to a subject undergoing vascular recanalization, said psoralen being administered in a safe and effective amount to achieve serum levels of psoralen appropriate for light-dependent inhibition of smooth muscle cell growth, recanalizing at least a partially-occluded vessel, and delivering ultraviolet radiation to the region of said recanalization in the presence of said psoralen.
2. The method of claim 1 in which the psoralen is substituted at one or more of the 3, 4, 5, 5' or 8 positions.
3. The method of claim 2 in which the substituents are methyl or methoxy.
4. The method of claim 3 in which the psoralen is
8-methoxypsoralen. The method of claim 1 in which the psoralen is administered orally. 6. The method of claim 5 in which the ultraviolet radiation is from about 320 to about 400 nm. 7. The method of one of claims 1-6 in which the sequence of steps and is reversed. 8. A method for preventing restenosis following coronary angioplasty which comprises: systemically administering a photoactivatable psoralen to a subject undergoing coronary angioplasty, said psoralen being administered in a safe and effective amount to achieve serum levels of psoralen S WO 92/18122 PCT/US92/02820 -13- appropriate for light-dependent inhibition of smooth muscle cell growth, reconfiguring at least a partially-occluded coronary artery by coronary angioplasty, and delivering ultraviolet radiation by fiber-optic means to the endoluminal surface of the artery in the region of said angioplasty.
9. The method of claim 8 in which the psoralen is substituted at one or more of the 3, 4, 5, 5' or 8 positions. The method of claim 9 in which the substituents are methyl or methoxy.
11. The method of claim 10 in which the psoralen is 8-methoxypsoralen.
12. The method of claim 8 in which the psoralen is administered orally.
13. The method of claim 12 in which the ultraviolet radiation is from about 320 to about 400 nm.
14. The method of one of claims 8-13 in which the sequence of steps and is reversed. A method for preventing restenosis in f peripheral or cardiac vasculature following vascular recanalization which comprises: systemically administering a photoactivatable psoralen to a subject undergoing vascular recanalization, said psoralen being administered in an amount sufficient to achieve serum -levels from about 0.1 to about 10 MM, recanalizing at least a partially- occluded vessel, and delivering ultraviolet radiation to the region of said recanalization in the presence of said psoralen. S WO 92/18122 PCT/US92/02820 -14-
16. The method of claim 15 in which the psoralen is substituted at one or more of the 3, 4, 5, 5' or 8 positions.
17. The method of claim 16 in which the psoralen is selected from the group of 8-methoxypsoralen, methoxypsoralen, 4-methylpsoralen, 4,4'- dimethylpsoralen, 4,5'-dimethylpsoralen, 4',8- dimethylpsoralen and 4,5',8-trimethylpsoralen.
18. The method of claim 15 in which the psoralen is 8-methoxypsoralen administered systemically in an amount sufficient to achieve serum levels of from about 0.1 to about 10 MM.
19. The method of one of claims 15-18 in which the ultraviolet radiation is from about 320 to about 400 nm. The method of one of claims 15-18 in which the sequence of steps and is reversed. -i Cc _LII- L I I lll~ INTERNATIONAL SEARCH REPORT International application No. PCT/US92/02820 A. CLASSIFICATION OF SUBJECT MATTER :A61K 31/35 US CL :514/455 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) U.S. 514/455 Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched NONE Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) NONE C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. US,A, 5,116,864 (MARCH ET AL) 26 MAY 1992 1-20 See entire document. A J. American College of Cardiology, Volume 15, number 7 issued June 1990, Dartsch et al. 1-20 responses of cultured smooth muscle cells-. pages 1545-1550 See entire document. O Further documents are listed in the continuation of Box C. See patent family annex. Special categories of cited documents: T" later document publihed after the international filing date or priority da and not in conflict with the application but cited to understand the "A documuendefinin the general oat of the art which i not consdered principle or theory underlying the invention to be pat of particular relevance *E erier d tl on or after the uteat mg date document of particular relevance; the claimed invention cannot be E' earier document publh on or after te internialioidered novel or cannot be considered to involve an inventive step document which may throw doubts on priority claim(s) or which i when the document i taken alone cited to etablish the publication date of another citation or other special reason (u specifid) document of particular relevance; the claimed invention cannot be conidered to involve an inventive step when the document is document referring to an oral discloure, use, exhibition or other combined with one or more other such document., such combination meau being obvious to a person skilled in the art documentpublbahe prior to the inerational filing date but later than document member of the same patent family the priority date claimed Date of the actual completion of the international search Date of mailing of the international search report 22 JULY 1992 14 E R 199 Name and mailing address of the ISA/ Authorized officer Commissioner of Patents and Trademarks Box l LEONARD SCHEK AN Washington, D.C. 20231 Facsimile No. NOT APPLICABLE Telephone No. (703) 308-4651 Form PCT/ISA/210 (second sheet)(July 1992)* I
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US682627 | 1991-04-09 | ||
US07/682,627 US5116864A (en) | 1991-04-09 | 1991-04-09 | Method for preventing restenosis following reconfiguration of body vessels |
PCT/US1992/002820 WO1992018122A1 (en) | 1991-04-09 | 1992-04-07 | Method for preventing restenosis following reconfiguration of body vessels |
Publications (2)
Publication Number | Publication Date |
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AU1875392A AU1875392A (en) | 1992-11-17 |
AU651701B2 true AU651701B2 (en) | 1994-07-28 |
Family
ID=24740491
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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AU18753/92A Ceased AU651701B2 (en) | 1991-04-09 | 1992-04-07 | Method for preventing restenosis following reconfiguration of body vessels |
Country Status (11)
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US (1) | US5116864A (en) |
EP (1) | EP0579784B1 (en) |
JP (1) | JPH06506695A (en) |
AT (1) | ATE186460T1 (en) |
AU (1) | AU651701B2 (en) |
CA (1) | CA2108025C (en) |
DE (1) | DE69230285T2 (en) |
DK (1) | DK0579784T3 (en) |
ES (1) | ES2141109T3 (en) |
GR (1) | GR3032623T3 (en) |
WO (1) | WO1992018122A1 (en) |
Families Citing this family (82)
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US5284869A (en) * | 1991-12-17 | 1994-02-08 | Emil Bisaccia | Photophoresis methods for treating atherosclerosis and for preventing restenosis following angioplasty |
US5910489A (en) * | 1990-09-18 | 1999-06-08 | Hyal Pharmaceutical Corporation | Topical composition containing hyaluronic acid and NSAIDS |
US5824658A (en) * | 1990-09-18 | 1998-10-20 | Hyal Pharmaceutical Corporation | Topical composition containing hyaluronic acid and NSAIDS |
CA2061703C (en) * | 1992-02-20 | 2002-07-02 | Rudolf E. Falk | Formulations containing hyaluronic acid |
US5116864A (en) * | 1991-04-09 | 1992-05-26 | Indiana University Foundation | Method for preventing restenosis following reconfiguration of body vessels |
US5990095A (en) | 1991-07-03 | 1999-11-23 | Hyal Pharmaceutical Corporation | Use of hyaluronic acid and forms to prevent arterial restenosis |
US6022866A (en) * | 1991-07-03 | 2000-02-08 | Hyal Pharmaceutical Corporation | Use of hyaluronic acid and forms to prevent arterial restenosis |
US5977088A (en) * | 1991-07-03 | 1999-11-02 | Hyal Pharmaceutical Corporation | Formulations containing hyaluronic acid |
US5222949A (en) * | 1991-07-23 | 1993-06-29 | Intermed, Inc. | Flexible, noncollapsible catheter tube with hard and soft regions |
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1991
- 1991-04-09 US US07/682,627 patent/US5116864A/en not_active Expired - Lifetime
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1992
- 1992-04-07 WO PCT/US1992/002820 patent/WO1992018122A1/en active IP Right Grant
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- 1992-04-07 DE DE69230285T patent/DE69230285T2/en not_active Expired - Fee Related
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AU1875392A (en) | 1992-11-17 |
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ES2141109T3 (en) | 2000-03-16 |
ATE186460T1 (en) | 1999-11-15 |
EP0579784A4 (en) | 1994-04-06 |
WO1992018122A1 (en) | 1992-10-29 |
CA2108025C (en) | 1998-08-04 |
JPH06506695A (en) | 1994-07-28 |
DK0579784T3 (en) | 2000-05-15 |
EP0579784A1 (en) | 1994-01-26 |
DE69230285D1 (en) | 1999-12-16 |
EP0579784B1 (en) | 1999-11-10 |
DE69230285T2 (en) | 2000-07-13 |
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